All Drugs and Chemicals

Tetrahydrouridine

Antimetabolites

Patients receive tetrahydrouridine PO on day 1; 5-fluoro-2-deoxycytidine PO on days 1 and 8; tetrahydrouridine IV over 3 hours on days 2-5, 8, and 9-12; and 5-fluoro-2-deoxycytidine IV over 3 hours on days 2-5 and 9-12 of course 1. For all subsequent courses, patients receive tetrahydrouridine IV over 3 hours and 5-fluoro-2-deoxycytidine IV over 3 hours on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

5-Fluoro-2-Deoxycytidine (FdCyd)

Laboratory Biomarker Analysis

Pharmacological Study

Tetrahydrouridine (THU)

Robert Morgan, MD

This phase I trial studies the side effects and best dose of 5-fluoro-2-deoxycytidine when given together with tetrahydrouridine in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Drugs used in chemotherapy, such as 5-fluoro-2-deoxycytidine and tetrahydrouridine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of 5-fluoro-2'-deoxycytidine (5-fluoro-2-deoxycytidine) (FdCyd) administered by intravenous (IV) infusion over three hours with concomitant infusion of 350 mg/m2 of tetrahydrouridine (THU).

II. To describe the toxicities of FdCyd co-infused with THU.

III. To obtain preliminary evidence of anti-tumor activity in patients treated with this combination.

IV. To evaluate the pharmacokinetics of FdCyd and THU when co-infused.

V. To evaluate the oral bioavailability of FdCyd when co-administered with THU.

VI. When feasible, to measure the relative levels of the messenger ribonucleic acid (mRNA)'s for thymidylate synthase, deoxycytidine kinase, deoxycytidylate (dCMP) deaminase and other relevant enzymes; and the methylation status of p16 and other genes relevant to neoplasia.

OUTLINE: This is a dose-escalation study of 5-fluoro-2-deoxycytidine. Patients receive tetrahydrouridine orally (PO) on day 1; 5-fluoro-2-deoxycytidine PO on days 1 and 8; tetrahydrouridine IV over 3 hours on days 2-5, 8, and 9-12; and 5-fluoro-2-deoxycytidine IV over 3 hours on days 2-5 and 9-12 of course 1. For all subsequent courses, patients receive tetrahydrouridine IV over 3 hours and 5-fluoro-2-deoxycytidine IV over 3 hours on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

5-Fluoro-2'-Deoxcyctidine and Tetrahydrouridine to Treat Patients With Advanced Cancer

Phase I Trial of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine

The relative levels of mRNA's of interest and other biochemical assessments will be tabulated and described. These levels will be compared with clinical response in an exploratory manner. However, the heterogeneity of the patient population and the small number of patients treated at each dose make formal statistical analysis of the molecular studies unlikely.

The pharmacokinetic data will be analyzed using compartmental and non-compartmental models for each patient. The estimated parameters will be tabulated by dose level with summary statistics (means and standard deviations, or medians and ranges). If appropriate, summary statistics will also be provided for the entire group of patients.

MTD is defined as the highest dose tested in which \< 33% of patients experienced dose limiting toxicity. The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by National Cancer Institute Common Toxicity Criteria version 2.0 and nadir or maximum values for the laboratory measures), time of onset (i.e., cycle number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by cycle.

Survival and time to failure will be summarized with Kaplan-Meier plots to describe the outcome of patients treated on this protocol.

National Cancer Institute (NCI)

City of Hope Medical Center

Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Neoplasm Metastasis

Melanoma

Sarcoma

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplastic Processes

Soft Tissue Sarcoma

Antineoplastic Agents

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

Decitabine

Celecoxib

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase 2 Inhibitors

Cyclooxygenase Inhibitors

Enzyme Inhibitors

Administered IV at increasing frequency or dose from 3-5 times per week for 8-12 weeks

decitabine (DAC)

400 mg orally twice a day every day for while on DAC-THU therapy

David S Schrump, M.D.

Background:

Most patients who have surgery for cancer that has metastasized (spread) to the lungs later get more metastases that cannot be treated with surgery or chemotherapy. The drug resistance may be due to DNA changes in cancer cells that activate some genes and turn others off. Researchers want to test a combination of drugs for people with metasteses. Decitabine (DAC) may reverse the DNA changes. Tetrahydrouridine (THU) makes DAC last longer. Celecoxib may slow the progression of cancer.

Objectives:

To determine a safe dose of DAC and THU by mouth. To see if DAC-THU with or without celecoxib reactivates genes in lung metastases.

Eligibility:

Adults 18 years and older, with cancer in both lungs that can be treated with surgery.

Design:

Participants will be screened with:

Blood, lung, and heart tests

Scans

Tests for viruses

Pregnancy test

Participants will have blood and stool tests.

They will have surgery to remove metasteses in 1 lung.

About 3 weeks later, they will have lung scans. If the disease is not back, participants will get DAC and THU with or without celecoxib, by mouth for 6 weeks.

Participants will have more scans. If the disease is not worse, they will continue the study drugs for 4 more weeks.

Participants will have more scans and heart and lung tests. They will have surgery to remove metasteses from the other lung.

Participants will have weekly blood and urine tests, plus several blood draws the first 2 days of taking the drugs.

Participants will have exams and blood tests before each surgery.

Participants will have follow-up visits 1 and 3 months after the second surgery.

Background:

* Whereas malignancies of diverse histologies express a variety of cancer testis antigens (CTAs), immune responses to these antigens appear uncommon in cancer patients, possibly due to low-level, heterogeneous antigen expression, as well as immunosuppressive regulatory T cells.
* In published studies we have demonstrated induction of NY-ESO-1 and MAGE-A3 in cancer cells of various histologies but not normal respiratory epithelial cells or fibroblasts following exposure to the DNA demethylating agent, Decitabine (DAC); up-regulation of these CTAs facilitated CTL-mediated lysis of tumor cells. We have also demonstrated eradication of pulmonary metastases in immunocompetent mice following systemic treatment with DAC and subsequent adoptive transfer of CTL recognizing the murine CTA, P1A. In a phase 1 trial, we demonstrated up-regulation of NY-ESO-1 and MAGE-A3 as well as reactivation of p16 in thoracic malignancies following intravenous 72hr DAC infusions. Chronic administration schedules are necessary for optimal gene induction in solid cancers.
* Additional studies using murine tumor models suggest that DNA demethylating agents may enhance the activity of immune checkpoint inhibitors not only by upregulating antigen presentation, but by inhibiting activity of myeloid derived suppressor cells (MDSC).
* Presently, there is no information regarding gene modulation and antitumor activity of oral epigenetic therapy in patients with solid tumors.
* In this study, the optimal frequency/dose of DAC-THU administration will be established in patients with bilateral pulmonary metastases, then an additional cohort of patients will receive DAC-THU together with celecoxib to inhibit activity of immunosuppressive Treg and myeloid derived suppressor cells. Correlative experiments will be performed to ascertain if oral epigenetic therapy modulates gene expression in pulmonary metastases and enhances antitumor immunity to these neoplasms.
* This trial is intended to establish the rationale and conditions for the use of oral DAC-THU +/- celecoxib in combination with immune checkpoint inhibitors or adoptive immunotherapy regimens targeting CTAs in patients with thoracic malignancies.

Objectives:

-To determine the pharmacokinetics, toxicities and maximum tolerated dose of oral DAC and THU with or without celecoxib in patients undergoing resection of pulmonary metastases

Eligibility:

* Patients with histologically or cytologically proven sarcoma, melanoma, germ cell tumors, or epithelial malignancies with bilateral pleuro-pulmonary metastases who can be rendered no clinical evidence of active disease (NED) or minimal residual disease (MRD) by metastasectomy.
* Patients greater than or equal to 18 years; ECOG performance status of 0-2, without evidence of unstable or decompensated myocardial disease; must have adequate pulmonary reserve evidenced by post-operative FEV1 and DLCO (Bullet) 40% predicted; pCO2 \< 50 mm Hg and pO2 \> 60 mm Hg on room air ABG; and be on no immunosuppressive medications except non-systemic corticosteroids.
* Patients must have a platelet count \> 100,000, ANC greater than or equal to 1500 without transfusion or cytokine support, a normal PT, and adequate hepatic function as evidenced by a total bilirubin of \< 1.5 times ULN. Serum creatinine less than or equal to 1.6 mg/ml or creatinine clearance \> 70 ml/min/1.73m(2) at the time DAC/THU +/- celecoxib treatment commences.

Design:

* Eligible subjects with bilateral pulmonary metastases will undergo disease resection in one hemithorax
* Following recovery from initial hemithoracic metastasectomy (approximately 2-3 weeks), patients will begin oral DAC (0.2mg/kg)-THU (10 mg/kg) therapy 3-5 consecutive days/week depending on dose level. THU will be administered 60 minutes prior to DAC.
* If no dose limiting systemic toxicities (primarily myelosuppression) are observed, the frequency of DAC- THU will be sequentially increased to maximize intra-tumoral DNMT1 depletion while avoiding grade 3 or greater systemic toxicities.
* Once the frequency of DAC-THU therapy has been optimized, additional patients will also receive oral celecoxib (400mg PO BID).
* Oral DAC-THU +/- celecoxib therapy will continue for 6 weeks. Patients will then have repeat imaging studies. Those patients who exhibit no evidence of disease recurrence in the operated lung with disease progression in the contralateral hemithorax will undergo metastasectomy if there are no standard of care contraindications such as progression of disease in extrathoracic sites. Those patients exhibiting response to therapy evidenced by stable or regressing nodules will continue DAC-THU therapy for 4 additional weeks, followed by metastasectomy.
* Systemic toxicities and response to therapy will be recorded. Gene expression and DNA methylation profiles in pre- and post-treatment metastases will be compared to determine if DAC-THU therapy has altered the epigenome of the metastases. Serologic responses to upregulated CTAs as well as cell mediated responses to epigenetically-modified autologous EBV-transformed B and autologous tumor cells (if available) will be assessed before and after treatment if there is evidence of CT gene activation following DAC-THU +/- celecoxib treatment.
* DNMT and CTA expression levels in PBMC and tumor tissues will be evaluated before and after treatment to ascertain if DAC-THU depletes systemic DNMT levels, and to determine if alterations in DNMT/CTA expression in PBMC can serve as surrogates of respective drug induced changes in tumor tissues.
* Following complete metastasectomy, patients will be followed in the clinic with routine staging scans per standard of care guidelines.
* As the exact set of comparisons and analyses to be performed will be determined following completion of the trial, and will be based on limited numbers of patients, the analyses will be considered exploratory and hypothesis generating rather than definitive.
* Approximately 46 patients will be accrued to this trial.

Adjuvant Oral Decitabine and Tetrahydrouridine With or Without Celecoxib in People Undergoing Pulmonary Metastasectomy

Phase I Evaluation of Adjuvant Oral Decitabine and Tetrahydrouridine With or Without Celecoxib in Patients Undergoing Pulmonary Metastasectomy

Respiratory Tract (Lung and Bronchial) Diseases

Digestive System Diseases

Carcinoma, Non-Small-Cell Lung

Carcinoma

Lung Neoplasms

Esophageal Neoplasms

Mesothelioma

Mesothelioma, Malignant

Neoplasms, Glandular and Epithelial

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Adenoma

Neoplasms, Mesothelial

Pleural Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Head and Neck Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Esophageal Cancer

Malignant Mesothelioma

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at escalating doses

Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at the dose established in Arm 1

Administered orally on two consecutive days (preferably Tuesday and Wednesday) for two weeks out of three weeks x 9 weeks

Decitabine (DAC)

200 mg intravenous (IV) once a day every Wednesday, Thursday or Friday every 3 weeks.

Background:

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Lung cancer is the leading cause of cancer-related death in the United States. Most people with lung cancer are already in the advanced stages of the disease by the time they see a doctor. Researchers want to see if combining an approved drug with two new drugs can help.

Objective:

To study if tetrahydrouridine-decitabine (THU-DAC) with pembrolizumab is safe and effective in people with non-small cell lung cancer that cannot be removed by surgery.

Eligibility:

People 18 years and older who have NSCLC that cannot be removed by surgery

Design:

Participants will be screened with

* Medical history
* Physical exam
* Blood and urine tests
* Tests of heart and lung function

They may have a small tumor sample taken (biopsy). They may have tumor scans.

Before starting treatment, participants will repeat the screening tests. They will also give a stool sample.

The study will be done in 3-week cycles for up to 6 cycles.

* Participants will take the 2 study drugs by mouth 3-5 days a week.
* Participants will get pembrolizumab in a vein for 30 minutes 1 day each cycle.

Participants will keep a study medication diary.

During cycle 1, participants will have blood taken multiple times on days 1 and 2.

Every 3 cycles, participants will repeat screening tests.

Participants will have a mandatory tumor biopsy.

When they finish treatment, participants will have a physical exam and blood tests.

Background:

* Non-small cell lung cancers (NSCLC) esophageal cancer (EsC) and malignant pleural mesotheliomas (MPM) account for approximately 185,000 deaths annually in the United States, with over two thirds of patients presenting with advanced, incurable disease. 1st-line platinum-based chemotherapy for advanced NSCLC, esophageal cancer (ESCs) or malignant pleural mesothelioma (MPM) produces transient responses at best, with most patients succumbing to disease within 12-16 months following diagnosis.
* Recent randomized clinical trials have demonstrated response rates approximating 20% in unselected patients with advanced NSCLC or EsC, and nearly 45% in patients with tumors exhibiting high level expression of programmed death ligand 1 (PD-L1) following administration of pembrolizumab, a humanized monoclonal anti-Programmed cell death protein 1 (PD-1) antibody.
* Approximately 17% of unselected MPM patients have exhibited objective responses following administration of pembrolizumab or other PD-1 inhibitors.
* Preclinical studies have demonstrated that epigenetic drugs such as deoxyribonucleic acid (DNA) demethylating agents and histone deacetylase (HDAC) inhibitors can prime cancer cells and tumor microenvironments thereby enhancing efficacy of immune checkpoint inhibitors.
* Although a potent DNA demethylating agent, Decitabine has poor bioavailability and inconsistent distribution in solid tumors due to rapid inactivation by cytidine deaminase (CDA) which is present in high levels in many organs.
* Recent studies in rodents and nonhuman primates, as well as a Phase 1 clinical trial (NCT#01685515) in patients with sickle cell disease have demonstrated that oral tetrahydrouridine (THU), an inhibitor of CDA, significantly enhances bioavailability/solid-tissue-distribution of low dose oral Decitabine (DAC), thereby enhancing systemic DNA demethylation with acceptable toxicities.
* Preliminary results of recent clinical trial suggest that oral DAC-THU can increase the frequency and magnitude of responses to immune checkpoint inhibitors in lung cancer patients with low or absent intra-tumoral PD-L1 expression.
* These data support further evaluation of oral DAC-THU in combination with immune checkpoint inhibitors for therapy of thoracic malignancies.

Objectives:

Phase I

-To define pharmacokinetics, toxicities and maximum tolerated dose of oral DAC-THU in combination with pembrolizumab in patients with inoperable, or unresectable locally advanced or metastatic NSCLC, EsC, or MPM.

Phase II

-To determine clinical response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria to oral DAC-THU in combination with pembrolizumab in patients with inoperable, or unresectable, locally advanced or metastatic NSCLC, EsC, or MPM.

Eligibility:

Inclusion Criteria

* Male or female, 18 years or older with histologically or cytologically proven, inoperable, or unresectable locally advanced, or metastatic NSCLC, EsC, or MPM.
* Measurable disease.
* Patients with high PD-L1 expression ((Bullet) 50%) and low PD-L1 expression (0-49%) in cancer cells by immunohistochemistry are eligible.
* NSCLC patients with no prior systemic treatment, or those with prior first line treatment including an immune checkpoint inhibitor are eligible for study.
* MPM patients who have received, refused, or are ineligible for first line chemotherapy are eligible.
* Patients with EsC including Seiwert-Stein Type I and Type II gastro-esophageal junction (GEJ) carcinomas who have received or refused standard of care first line therapy and/or targeted therapy are eligible.
* Patients who received DNA demethylating agents or PD-1/PD-L1 inhibitors for another malignancy may be eligible for study if there were no dose-limiting immune related events, and there has been either no clinical evidence of disease or minimal residual disease that has been stable for at least three years.
* Willingness to undergo tumor biopsies if safely accessible per PI discretion before and after treatment.
* Eastern Cooperative Oncology Group (ECOG) performance status 0 2.
* No evidence of unstable or decompensated myocardial disease; adequate pulmonary reserve.
* Adequate renal, hepatic and hematopoietic function.

Exclusion Criteria

* Patients with any targetable mutation for which there is approved first, or second line therapy.
* Serious cardiovascular conditions.
* Active Hepatitis A, Hepatitis B or Hepatitis C.
* Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
* Other active infection requiring systemic therapy.
* Pregnant or breastfeeding women.
* Patients who are receiving systemic corticosteroids.
* Patients receiving another investigational agent.
* Another malignancy.

Design:

* The Phase I component will be a standard 3+3 design combining high and low PD-L1 expressers with incremental dose escalation of oral DAC-THU to define maximum tolerated dose (MTD).
* Simon 2-stage design for Phase II studies will be used to determine clinical response at the MTD.
* Patients will receive oral DAC-THU- on T-W for two weeks out of every 3 for 9 weeks
* Pembrolizumab will be administered on Wednesday, Thursday or Friday at a fixed intravenous dose of 200 mg every 3 weeks.
* One cycle is three weeks; one course is 9 weeks. Treatment evaluation using RECIST 1.1 every 10 +/- 1 weeks.
* Those patients exhibiting disease progression or unacceptable toxicities will be removed from study. Patients exhibiting stable disease or disease regression will be offered an additional course of therapy followed by treatment evaluation. Treatment will continue in this manner until off-study criteria have been met.
* Once the MTD for DAC/THU has been identified, the MTD dose level will be expanded by 4 patients to confirm its safety. Then, including these 10 patients at the MTD, a total of 10 NSCLC patients with high (50% or greater) intratumoral PD-L1 expression and 10 NSCLC patients with low (0-49%) intratumoral PD-L1 expression will be accrued to the first stage of each of two separate Phase II cohorts using individual Simon optimal designs. If 5 or more patients of the 10 first stage NSCLC patients in the high PD-L1 cohort respond to treatment, the cohort will be expanded to 23 patients. If 11 of 23 of these patients respond to treatment, the trial will be deemed positive for NSCLC with high PD-L1 expression. If 2 or more of the 10 first stage NSCLC patients in the low PD-L1 expression cohort respond to treatment, the cohort will be expanded to 29 patients. If 6 or more of these 29 patients experience a response, the trial will be deemed positive for NSCLC with low PD-L1 expression. Up to 10 EsC patients, including those considered to be part of the Phase I component after the MTD has been identified, will be enrolled into a separate cohort to examine responses to DAC-THU/pembrolizumab at the MTD. If 2 or more of these 10 EsC patients respond to treatment, these findings may warrant an amendment or a separate Phase II trial to determine response rates to DAC-THU/pembrolizumab in EsC patients. Similarly, if 2 or more of 10 MPM patients respond to treatment, these findings may warrant an amendment or a separate Phase II trial to determine response rates to DACTHU/pembrolizumab in MPM.
* Biopsies of index lesions will be obtained at baseline and at treatment evaluation following the first course of therapy for analysis of pharmacodynamic endpoints.
* Patients will be followed for toxicity for at least 30 days after treatment has been discontinued, start of new anti-cancer treatment or until death, whichever occurs first.

Oral Decitabine and Tetrahydrouridine as Epigenetic Priming for Pembrolizumab-Mediated Immune Checkpoint Blockade in Patients With Inoperable, or Unresectable Locally Advanced or Metastatic Non-Small Cell Lung Cancers and Esophageal Carcinomas

Phase I/II Evaluation of Oral Decitabine/Tetrahydrouridine as Epigenetic Priming for Pembrolizumab Immune Checkpoint Blockade in Inoperable Locally Advanced or Metastatic Non-Small Cell Lung Cancers, Esophageal Carcinomas, or Pleural Mesotheliomas

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the Database of Genotypes and Phenotypes (dbGaP).

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

A DLT is any Grade 3 (severe) or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.

Overall response rate was measured using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 to determine if the combination of decitabine and tetrahydrouridine is associated with a response rate which exceeds that of Pembrolizumab alone in participants who have programmed death-ligand 1 (PD-L1) expression of at least 50% and those who do not. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.

Maximum Tolerated Dose (MTD) is the maximum dose at which fewer than one-third of participants experience dose limiting toxicity (DLT) within the first 6 weeks (two cycles) of decitabine and tetrahydrouridine therapy. If one of three patients at any given dose level experiences DLT, up to three additional patients will be treated at this dose level. If only one of six patients exhibit DLT, subsequent patients will be enrolled into the next higher dose level. As soon as two patients at any given dose level develop DLT, no additional patients will be entered at that level. Subsequent patients will be accrued into the preceding dose level; if DLT is observed in less than two of six patients treated at this lower level, this dose will represent maximum tolerated dose (MTD). A DLT is any Grade 3 or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.

Peripheral blood will be collected to correlate changes in circulating tumor cells with clinical response. CTCs will be assessed using ferrofluidic enrichment and multi-parameter flow cytometric detection. Baseline and post-treatment specimen collection after one course of therapy (Week 10 +/- one week).

Peripheral blood mononuclear cells (PBMC) will be assessed using multiparameter flow cytometry for immune subsets including but not necessarily limited to Tregs, myeloid-derived suppressor cells (MDSC), effector and exhausted cluster of differentiation 4 (CD4+), cytotoxic T lymphocytes (CD8+) T cells, and cluster of differentiation 14 (CD14 +) monocytes. Assessment will include functional markers, i.e., programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM-3), cluster of differentiation 152 (CTLA-4), human leukocyte antigen (HLA) membrane heterodimeric glycoproteins (-DR) and/or cluster of differentiation 40 (CD40). Baseline and post-treatment specimen collection after one course of therapy (Week 10 +/- one week).

Portions of biopsy materials will be sent for frozen section or permanent section confirmation of malignancy, i.e., non-small cell lung cancers (NSCLC), esophageal carcinomas (Esc), malignant pleural mesothelioma (MPM) cells, and percent viable tumor cells. All of the analyses are predicated on acquisition of sufficient materials.

Tissue will be processed for focused gene, endogenous retroviral and microRNA expressions, and DNA methylation signatures using quantitative reverse-transcription polymerase chain reaction (RT-PCR), nanostring, pyrosequencing and digital droplet PCR techniques. Isolate serum for focused methylation analysis. If sufficient tissue is available, another portion will be imbedded in paraffin for subsequent immunostaining experiments, focusing on expression of genes focusing on those proteins encoded by genes that have been identified to be clearly activated by epigenetic therapy. If sufficient materials are present, additional more comprehensive analyses including multiplex immunohistochemistry analysis of tumor microenvironment may be performed with the focus of materials from participants treated at the maximum tolerated dose. All of the analyses are predicated on acquisition of sufficient materials.

Principal Investigator

1/9 participants did not receive any therapy.

Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level 1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT) q week with Pembrolizumab infusion q3weeks

Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT)

Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level -1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT) q week. Participants received Pembrolizumab infusion q3weeks.

Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT)

Phase 1, Arm 1, Dose Escalation, Revised Dose Level 1. Participants received Decitabine 0.21 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.

Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks

Phase 1, Arm 1, Dose Escalation, Revised Dose Level -1. Participants received Decitabine 0.17 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.

Decitabine 0.17mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks

Participants who were enrolled but not treated.

Enrolled to Revised Dose Level 1 But Not Treated

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

No participants were enrolled on Decitabine 0.17mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks.

Dr. David S. Schrump

Complete Response

Partial Response

Stable Disease

Progressive Disease

Unevaluable for response

Overall Response Rate

Maximum Tolerated Dose (MTD) of Decitabine

Maximum Tolerated Dose (MTD) of Tetrahydrouridine

This outcome measure was not evaluated and was to be performed in bulk. No assays were performed due to the pandemic. Participants could not travel to the National Institutes of Health (NIH) to have samples drawn.

Changes in Circulating Tumor Cells (CTCs)

Changes in Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMC)

This outcome measure was not done because 1 participant declined biopsy due to the pandemic. And one participant did not have adequate tissue to evaluate. All other participants did not have biopsies.

Percent Viable Tumor Cells

Changes in Gene, Endogenous Retroviral (ERV), Micro Ribonucleic Acid (RNA) Expressions, Deoxyribonucleic Acid (DNA) Methylation Signatures and Tumor Microenvironment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
5-Fluoro-2'-Deoxcyctidine and Tetrahydrouridine to Treat Patients With Advanced Cancer	NCT00359606	Neoplasms	5-Fluoro-2-Deox... Laboratory Biom... Pharmacological... Tetrahydrouridi...	18 Years -	City of Hope Medical Center
Adjuvant Oral Decitabine and Tetrahydrouridine With or Without Celecoxib in People Undergoing Pulmonary Metastasectomy	NCT02839694	Neoplasm Metast... Sarcoma Neoplasms, Germ... Melanoma	decitabine (DAC... Tetrahydrouridi... Celecoxib	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
5-Fluoro-2'-Deoxcyctidine and Tetrahydrouridine to Treat Patients With Advanced Cancer	NCT00359606	Neoplasms	5-Fluoro-2-Deox... Laboratory Biom... Pharmacological... Tetrahydrouridi...	18 Years -	City of Hope Medical Center
Oral Decitabine and Tetrahydrouridine as Epigenetic Priming for Pembrolizumab-Mediated Immune Checkpoint Blockade in Patients With Inoperable, or Unresectable Locally Advanced or Metastatic Non-Small Cell Lung Cancers and Esophageal Carcinomas	NCT03233724	Carcinoma, Non-... Lung Cancer Non-Small Cell ... Carcinoma, Esop... Malignant Pleur...	Decitabine (DAC... Tetrahydrouridi... Pembrolizumab	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for tetrahydrouridine (thu)